As life expectancy of HIV-positive (HIV+) patients has increased for those receiving highly active antiretroviral therapy (HAART), chronic complications from smoking contribute substantially to morbidity and mortality. We have demonstrated that chronic obstructive lung disease (OLD) is an important problem and is more prevalent in HIV+ compared to HIV-negative (HIV-) patients, after adjusting for smoking and other confounding factors. Smoking is also a risk factor for other diseases that are increased in HIV, namely lung cancer, bacterial pneumonia, tuberculosis, and Pneumocystis pneumonia. We hypothesize that HIV+ patients have enhanced susceptibility to the consequences of smoking. Those who smoke and have HIV may be more predisposed to lung injury as a result of increased oxidative stress, which is known to be elevated in the setting of HIV,as well as in smoking and OLD. Our first aim is to 1) compare the incidence, risk factors, and outcomes for lung disease in HIV+ to HIV- patients. We will determine the independent risk for lung disease conferred by HIV infection, and to what extent the risk of lung complications is related to smoking or to concomitant OLD. These analyseswill be conducted within an ongoing, large, multicenter, prospective observational study of HIV+ and HIV- subjects, the Veterans Aging Cohort Study that has recently had funding renewed through 2011. Studies for Aims 2 and 3 will focus in-depth on a smaller group of subjects to understand clinical and pathophysiologic differences in OLD between HIV+ and HIV-patients. We hypothesize that OLD progresses more rapidly in HIV+ compared to HIV- smokers and that the accelerated progression is related to increased oxidative stress. We will obtain baseline and serial evaluations of pulmonary function, peripheral blood, exhaled breath condensates, and bronchoalveolar lavage specimens in HIV+ and HIV-current and former smokers with or at risk for OLD. Additional aims are to 2) compare risk factors for progression of OLD in HIV+ and HIV- smokers, and 3) compare markers of oxidative stress and progression of OLD in HIV+ and HIV- smokers. The studies proposed are poised to increase our understanding of lung diseases in HIV+ patients and to yield results that can be used directly to improve patient care. Furthermore, insights into reasons for susceptibility to OLD and accelerated progression of OLD can improve care for both HIV+ and HIV-patients.